Crifos

Uses

Crifos is used only for the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis. Crifos is not used for the treatment of pyelonephritis or perinephric abscess.

If persistence or reappearance of bacteriuria occurs after treatment with Crifos, other therapeutic agents should be selected.

Crifos is also used to associated treatment for these conditions: Complicated Urinary Tract Infection, Uncomplicated Urinary Tract Infections caused by E. coli, Uncomplicated Urinary Tract Infections caused by Enterococcus faecalis

How Crifos works

Crifos exerts its bactericidal effects by binding covalently to a cysteine in the active site of the UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme, rendering it inactive. By preventing MurA from catalyzing the condensation of phosphoenolpyruvate (PEP) with UDP-N-acetylglucosamine (UNAG), fosfomycin inhibits the production of the peptidoglycan precursor UDP N-acetylmuramic acid (UDP-MurNAc). Ultimately, the first step of bacterial cell wall synthesis is disrupted.

In Escherichia coli, fosfomycin gains entry into bacterial cells via two mechanisms: the L-alpha-glycerophosphate system and the hexose-6-phosphate transporter system.

Crifos also has important effects on cell adhesion. For example, the adhesion of bacterial cells to urinary epithelial cells is reduced in the presence of fosfomycin. The adhesion of Streptococcus pneumoniae and Haemophilus influenzae to respiratory epithelial cells is also reduced

Dosage

Crifos dosage

The recommended dosage for women 18 years of age and older for uncomplicatedurinary tract infection(acute cystitis) is one sachet (3 gm) of Crifos. Crifos may be taken with or without food. Crifos should not be taken in its dry form. Always mix Crifos with water before ingesting.

Preparation: Pour the entire contents of a single-dose sachet of Crifos into 3 to 4 ounces of water (½ cup) and stir to dissolve. Do not use hot water. Crifos should be taken immediately after dissolving in water.

Side Effects

Most frequently reported adverse events occurring in more than 1%: diarrhea 10.4%, headache 10.3%, vaginitis 7.6%, nausea 5.2%, rhinitis 4.5%, back pain 3.0%, dysmenorrheal 2.6%, pharyngitis 2.5%, dizziness 2.3%, abdominal pain 2.2%, pain 2.2%, dyspepsia 1.8%, asthenia 1.7%, and rash 1.4%.

The following adverse events occurred less than 1%: abnormal stools, anorexia, constipation, dry mouth, dysuria, ear disorder, fever, flatulence, flu syndrome, hematuria, infection, insomnia, lymphadenopathy, menstrual disorder, migraine, myalgia, nervousness, paresthesia, pruritus, SGPT increased, skin disorder, somnolence, and vomiting.

Toxicity

Acute toxicology studies have found that oral fosfomycin doses 50-125 times the human therapeutic dose were well-tolerated in rats and mice, resulted in minor and transient watery stools in rabbits, and caused diarrhea with anorexia in dogs 2-3 days after single-dose administration.

In humans, symptoms of overdose have included impaired hearing, vestibular loss, general decline in taste perception, and metallic taste. In the event of overdose, the patient should be managed with symptomatic and supportive measures.

Precaution

General: Do not use more than one single dose of Crifos to treat a single episode of acute cystitis. Repeated daily doses of Crifos did not improve the clinical success or microbiological eradication rates compared to single dose therapy, but did increase the incidence of adverse events. Urine specimens for culture and susceptibility testing should be obtained before and after completion of therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term carcinogenicity studies in rodents have not been conducted because Crifos is intended for single dose treatment in humans. Crifos was not mutagenic or genotoxic in the in vitro Ames' bacterial reversion test, in cultured human lymphocytes, in Chinese hamster V79 cells, and the in vivo mouse micronucleus assay. Crifos did not affect fertility or reproductive performance in male and female rats.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Crifos, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Clostridium difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Crifos Disease Interaction

Major: colitisModerate: hemodialysisMinor: renal dysfunction

Volume of Distribution

In healthy subjects, the volume of distribution (Vd) of fosfomycin is approximately 0.3 L/Kg. Due to changes in the vascular endothelium, the Vd can be up to 50% higher in critically ill patients.

Elimination Route

Crifos is a low molecular weight and hydrophilic drug. When administered orally, fosfomycin is rapidly absorbed in the small intestine and distributed widely to the tissues. The oral bioavailability ranges from 34-58%. Co-administration of fosfomycin with food decreases gastrointestinal absorption to approximately 30%. The reported AUC = 145-228 mg x h/L, while the reported Cmax = 26.1 (∓9.1) mcg/mL.

Half Life

The mean elimination half-life of fosfomycin is 5.7 (∓2.8) hours.

Clearance

In one study, the reported CL/F of fosfomycin in healthy volunteers was 17 ∓ 4.7 L/hour.

Elimination Route

Crifos is excreted almost entirely by the kidneys. Factors including administration with food, impaired renal function, and older age may reduce the rate of fosfomycin elimination.

Pregnancy & Breastfeeding use

Pregnancy Category B. It is not known whether fosfomycin tromethamine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Crifos, a decision should be made whether to discontinue nursing or to not administer the drug, taking into account the importance of the drug to the mother.

Contraindication

Crifos is contraindicated in patients with known hypersensitivity to the drug.

Special Warning

Pediatric Use: Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.

Geriatric Use: Clinical studies of Crifos did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Acute Overdose

In acute toxicology studies, oral administration of high doses of Crifos up to 5 gm/kg were well-tolerated in mice and rats, produced transient and minor incidences of watery stools in rabbits, and produced diarrhea with anorexia in dogs occurring 2-3 days after single dose administration. These doses represent 50-125 times the human therapeutic dose.

The following events have been observed in patients who have taken Crifos in overdose: vestibular loss, impaired hearing, metallic taste, and general decline in taste perception. In the event of overdosage, treatment should be symptomatic and supportive.

Storage Condition

Store at 25°C; excursions permitted to 15-30°C.

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